The ergoline ring is a tetracycle having the following structure ##STR1##
Certain substituted ergolines are known to be D-2 dopamine agonists having the ability to inhibit the secretion of prolactin and to affect favorably the symptoms of Parkinson's Syndrome. For example, in the foregoing structure when R is n-propyl, R.sup.1 is methylthiomethyl, and R" is H, the substituted ergoline has been given the generic name pergolide, which is disclosed in U.S. Pat. No. 4,166,182. Pergolide has been proven to be effective in the treatment of some symptoms of Parkinsonism, and is being developed as the mesylate salt. Another such ergoline drug is .alpha.-bromo-ergocryptine, named generically as bromocryptine. It is disclosed in U.S. Pat. Nos. 3,752,814 and 3,752,888. For bromocryptine, R" is Br, R is methyl and R' is the ergocryptine side chain. While both ergolines are D-2 dopamine agonists, bromocryptine and pergolide also act at .alpha. adrenergic receptors.
BCD tricyclic ergoline part-structure compounds having the following formula ##STR2## wherein R is lower alkyl, have been synthesized, and are disclosed in Bach et al., J. Med. Chem., 23, 481 (1980) and U.S. Pat. No. 4,235,909. These products were prepared as racemates composed of the enantiomer illustrated above together with the mirror image thereof. In both enantiomers the R' substituent is equatorial. These compounds show activity in prolactin inhibition and rat-turning behavior tests, indicating that D-2 dopamine agonist activity is present. Related compounds in which the C-1 carbon is replaced by nitrogen to form a pyrazole ring are also disclosed by Bach et al. in J. Med. Chem., 23, 481 (1980) and in U.S. Pat. No. 4,198,415. These pyrazoloquinolines are also D-2 dopamine agonists. They were prepared as the optically active isomers. See J. Med. Chem., 26, 1112 (1983) and U.S. Pat. No. 4,567,266.
Other BCD tricyclic ergoline part-structure compounds having the following general formula ##STR3## wherein the C- and D-rings are trans-fused and wherein the B-ring may be either a pyrimidine, thiazole, pyrazole, oxazole or pyrrole ring are disclosed in U.S. Pat. No. 4,826,986. These compounds are also D-2 dopamine agonists, and are prepared as racemates.
A number of diseases which have inflammatory components, beset mankind. Rheumatoid arthritis, contact hypersensitivities, and autoimmune syndromes are but a few examples of inflammatory processes which are driven by aberrant or uncontrolled activity of the immune system. Thus, it is not surprising that frequently, treatment of such inflammatory states has focused on disrupting the underlying immunological response, which in turn results in the abatement of the inflammatory manifestations of such disease states. Examples of clinical agents used in this approach include cyclosporine and methotrexate.
A significant limitation to the "treat the immunological aspect and the inflammation will subside" approach is the compromised immunological state of the host thus treated and the resultant vulnerability of the host to viral, bacterial and fungal infections as well as the potential for outgrowth of tumors which heretofore were held in check by an uncompromised immune system.
The alternate approach to clinical management of inflammatory diseases involves treatment with known anti-inflammatory agents such as steroids or preferably with non-steroidal anti-inflammatory drugs. Steroids are disfavored due to the numerous complications arising from therapy therewith. Likewise, the toxicities associated with many of the non-steroidal anti-inflammatory agents (NSAIDs) severely limits the clinical utility of NSAIDs.
The spectrum of inflammatory disease states, which lack a safe and effective therapy, presents a significant clinical problem. This problem is answered, in part, by the discovery that ergolines, possess anti-inflammatory activity. Surprisingly, the anti-inflammatory activity of the ergolines is not mediated by immunosuppressive effects. Thus, the now discovered direct anti-inflammatory activity of members of the ergolines allows clinical utilization of ergolines which heretofore would have been reserved due to the erroneous presumption that their anti-inflammatory activity was like bromocryptine merely a secondary effect of immunosuppressive activity.
It is one object of the present invention to provide methods of treating inflammation, and the accompanying pain and swelling in man and animals by administering certain ergoline or BCD tricyclic ergoline part-structure compounds.
Further objects will become apparent to those skilled in the art from the following description and claims.